This invention relates to methods of treating cyclooxygenase mediated diseases and certain pharmaceutical compositions therefor.
Non-steroidal, antiinflammatory drugs exert most of their antiinflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme, as originally identified in bovine seminal vesicles. More recently the gene for a second inducible form of cyclooxygenase, cyclooxygenase-2 (COX-2) has been cloned, sequenced and characterized initially from chicken, murine and human sources. This enzyme is distinct from the COX-1 which has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man. The second form of cyclooxygenase, COX-2, is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. As prostaglandins have both physiological and pathological roles, we have concluded that the constitutive enzyme, COX-1, is responsible, in large part, for endogenous basal release of prostaglandins and hence is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, we have concluded that the inducible form, COX-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Thus, a selective inhibitor of COX-2 will have similar antiinflammatory, antipyretic and analgesic properties to a conventional non-steroidal antiinflammatory drug, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects, but will have a diminished ability to induce some of the mechanism-based side effects. In particular, such a compound should have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a lessened ability to induce asthma attacks in aspirin-sensitive asthmatic subjects.
Furthermore, such a compound will also inhibit prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of use in the treatment of dysmenorrhea, premature labour, asthma and eosinophil related disorders. It will also be of use in the treatment of Alzheimer's disease, for decreasing bone loss particularly in postmenopausal women (i.e. treatment of osteoporosis) and for the treatment of glaucoma.
The potential utilities of selective cyclooxygenase-2 inhibitors are discussed in the following articles:
1. John Vane, "Towards a better aspirin" in Nature, Vol. 367, pp. 215-216, 1994.
2. Bruno Battistini, Regina Botting and Y. S. Bakhle, "COX-1 and COX-2: Toward the Development of More Selective NSAIDs" in Drug News and Perspectives, Vol. 7, pp. 501-512, 1994. PA1 3. David B. Reitz and Karen Seibert, "Selective Cyclooxygenase Inhibitors" in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol. 30, pp. 179-188, 1995. PA1 4. Don E. Griswold and Jerry L. Adams, "Constituative Cyclooxygenase (COX-1) and Inducible Cyclooxygenase (COX-2): Rationale for Selective Inhibition and Progress to Date" in Medicinal Research Reviews, Vol. 16, pp. 181-206, 1996. PA1 Ar is a mono-, di-, or trisubstituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of PA1 R.sup.2 is chosen from the group consisting of PA1 R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, are each independantly chosen from the group consisting of PA1 or R.sup.4 and R.sup.5, R.sup.8 and R.sup.9 or R.sup.11 and R.sup.12 together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms. PA1 (a) hydrogen, PA1 (b) halo, PA1 (c) C.sub.1-4 alkoxy, PA1 (d) C.sub.1-4 alkylthio, PA1 (e) C.sub.1-4 alkyl, PA1 (f) CF.sub.3, and PA1 (g) CN. PA1 Ar is a mono-, di-, or trisubstituted pyridinyl (or the N-oxide thereof), wherein the substituents are chosen from the group consisting of PA1 R.sup.2 is chosen from the group consisting of PA1 R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11, R.sup.12, R.sup.13, are each independantly chosen from the group consisting of PA1 R.sup.2 is chosen from the group consisting of PA1 R.sup.2 is chloro, PA1 wherein there is one group X independently selected from the group consisting of PA1 R.sup.2 is chloro, PA1 wherein there is one group X independently selected from the group consisting of PA1 3-(4-Methylsulfonyl)phenyl-2-phenyl-5-trifluoromethylpyridine; PA1 2-(3-Chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine; PA1 2-(4-Chlorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine; PA1 2-(4-Fluorophenyl)-3-(4-methylsulfonyl)phenyl-5-trifluoromethyl-pyridine; PA1 3-(4-Methylsulfonyl)phenyl-2-(3-pyridinyl)-5-trifluoromethylpyridine; PA1 5-Methyl-3-(4-methylsulfonyl)phenyl-2-phenylpyridine; PA1 2-(4-Chlorophenyl)-5-methyl-3-(4-methylsulfonyl) phenylpyridine; PA1 5-Methyl-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl) pyridine; PA1 5-Chloro-2-(4-chlorophenyl)-3-(4-methylsulfonyl) phenylpyridine; PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-pyridinyl) pyridine; PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridinyl) pyridine; PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(4-pyridinyl) pyridine; PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; PA1 2-(4-Chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic acid methyl ester; PA1 2-(4-Chlorophenyl)-3-(4-methylsulfonyl)phenylpyridinyl-5-carboxylic acid; PA1 5-Cyano-2-(4-chlorophenyl)-3-(4-methylsulfonyl) phenylpyridine; PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridine hydromethanesulfonate; PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(3-pyridyl)pyridine hydrochloride; PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine Hydrochloride; PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridine; and PA1 5-Chloro-3-(4-methylsulfonyl)phenyl-2-(2-ethyl-5-pyridinyl)pyridine hydromethanesulfonate. PA1 a non-toxic therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. PA1 a non-toxic therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. PA1 administration to a patient in need of such treatment of a non-toxic therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier. PA1 AA=arachidonic acid PA1 Ac=acetyl PA1 AIBN=2.2-azobisisobutyronitrile PA1 BHT=butylated hydroxytoluene PA1 Bn=benzyl PA1 CSA=camphor sulfonic acid (racemic) PA1 dba=dibenzylideneacetone PA1 DMAP=4-(dimethylamino)pyridine PA1 DMF=N,N-dimethylformamide PA1 DMSO=dimethyl sulfoxide PA1 EDTA=ethylenediaminetetraacetic acid PA1 ESA=ethane sulfonic acid PA1 Et.sub.3 N=triethylamine PA1 HBSS=Hanks balanced salt solution PA1 HEPES=N-[2-Hydroxyethyl]piperazine-N.sup.1 -[2-ethanesulfonic acid] PA1 HWB=human whole blood PA1 KHMDS=potassium hexamethyldisilazane PA1 LDA=lithium diisopropylamide PA1 LPS=lipopolysaccharide PA1 mCPBA=m-chloroperbenzoic acid PA1 MMPP=magnesium monoperoxyphthalate PA1 Ms=methanesulfonyl=mesyl PA1 Ms0=methanesulfonate=mesylate PA1 MTBE=methyl tert-butyl ether PA1 NBS=N-bromosuccinimide PA1 NCS=N-chlorosuccinimide PA1 NIS=N-iodosuccinimide PA1 NMO=N-methylmorpholine-N-oxide PA1 NMP=N-methylpyrrolidone PA1 NSAID=non-steroidal anti-inflammatory drug PA1 oxone.RTM.=2KHSO.sub.5 KHSO.sub.4 K.sub.2 SO.sub.4 PA1 PCC=pyridinium chlorochromate PA1 PDC=pyridinium dichromate PA1 PEG=polyethyleneglycol PA1 Ph=phenyl PA1 pyr=pyridinyl PA1 r.t.=room temperature PA1 rac.=racemic PA1 Tf=trifluoromethanesulfonyl=triflyl PA1 Tf0=trifluoromethanesulfonate=triflate PA1 THF=tetrahydrofuran PA1 TLC=thin layer chromatography PA1 Ts=p-toluenesulfonyl=tosyl PA1 TsO=p-toluenesulfonate=tosylate PA1 Tz=1H (or 2H)-tetrazol-5-yl PA1 SO.sub.2 Me=methyl sulfone PA1 SO.sub.2 NH.sub.2 =sulfonamide PA1 Me=methyl PA1 Et=ethyl PA1 n-Pr=normal propyl PA1 i-Pr=isopropyl PA1 n-Bu=normal butyl PA1 i-Bu=isobutyl PA1 s-Bu=secondary butyl PA1 t-Bu=tertiary butyl PA1 c-Pr=cyclopropyl PA1 c-Bu=cyclobutyl PA1 c-Pen=cyclopentyl PA1 c-Hex=cyclohexyl PA1 bid - bis in die=twice daily PA1 qid=quater in die=four times a day PA1 tid=ter in die=three times a day PA1 0, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h PA1 PEG 200/300/400: restricted to 2 mL/kg PA1 Methocel 0.5%-1.0%: 10 mL/kg PA1 Tween 80: 10 mL/kg PA1 0, 5 min, 15 min, 30 min, 1 h, 2 h, 6 h or PA1 0, 5 min, 30 min, 1 h, 2 h, 4 h, 6 h. PA1 Dextrose: 1 mL/kg PA1 Moleculosol 25%: 1 mL/kg PA1 DMSO (dimethylsulfoxide): Restricted to a dose volume of 0.1 mL per animal PA1 PEG 200: Not more than 60% mixed with 40% sterile water--1 mL/kg PA1 (i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25.degree. C. and drying of organics was done using MgSO.sub.4, PA1 (ii) evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60.degree. C., PA1 (iii) the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; PA1 (iv) melting points are uncorrected and `d` indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations; PA1 (v) the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data; PA1 (vi) yields are given for illustration only; PA1 (vii) when given, NMR data is in the form of delta (d) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition "Ar" signifies an aromatic signal; PA1 (viii) chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (litre(s)), mL (millilitres), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)), r.t. (room temperature).
WO 96/10012 (DuPont Merck, Apr. 4, 1996) discloses compounds represented by Formula A as being useful in the treatment of COX-2 mediated diseases, by virtue of their selective inhibition of COX-2 rather than COX-1. We have now discovered that a subset of the compounds represented by A, in which --J--K--L--is --NCHCH--, X is a bond, R.sup.1 is aromatic and R.sup.3 and R.sup.4 are not both hydrogen show unexpectedly superior selectivity for the inhibition of COX-2 over COX-1 and/or superior potency as compared to the closest species disclosed in 96/10012. This subset of compounds is the subject of the present invention and is represented by Formula I. ##STR1##
Of the over 175 specific compounds disclosed in WO 96/10012, only 4 of them are pyridines, and none of these latter contain a substituent (R.sup.3 or R.sup.4 in A) on the pyridine ring.
WO 96/16934 (Searle, Jun. 6, 1996) discloses compounds represented by structure B as being useful for the treatment of inflammation and related disorders. Chemically, these compounds differ from those of the present invention in that the central of the three aromatic rings is benzene rather than pyridine.